Retinoid X receptor (hereinafter abbreviated as “RXR”) is one of nuclear receptors, which are ligand-dependent transcription factors, and is believed to make 9-cis retinoic acid and docosahexaenoic acid (DHA) into endogenous ligands. Its function is exerted as a homodimer or a heterodimer formed with various nuclear receptors (Nonpatent document No. 1).
As a heterodimer partner of RXR, in addition to retinoic acid receptor (RAR) involved in cell differentiation and proliferation, vitamin D receptor (VDR) likewise involved in cell differentiation and proliferation and also bone metabolism, peroxisome proliferator-activated receptor (PPAR) involved in lipid metabolism and thyroid hormone receptor (TR), there is PXR associated with the expression of CYP3A4, which is known as a drug-metabolizing enzyme. Therefore, as the function of RXR is closely connected to the active expression of these nuclear receptors, the agonists or antagonists which control the function of RXR can control the functions of these heterodimers (Nonpatent document No. 2).
For example, while RAR agonist Am80 (generic name: tamibarotene; an therapeutic agent for recurrent or intractable acute promyelocytic leukemia: 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) carbamoyl]benzoic acid: Nonpatent document No. 3) shows little cell differentiation-inducing action when present alone at a concentration of 3.3×10−10 M, the combined use of Am80 and RXR agonist allows the RXR agonist to function as a synergist of Am80, showing a significant differentiation-inducing action (Nonpatent document No. 4). Such synergistic effects exerted on nuclear receptor heterodimers by RXR agonists can be seen not only on RAR but also on VDR, PPAR and the like which form heterodimers with RXR. Namely, with a highly lipid-soluble pharmaceutical molecule which targets such a nuclear receptor, synergistic effects can be obtained even with a low dose of that drug.
Further, RXR antagonist can selectively inhibit the function of a heterodimer containing RXR. For example, RXR antagonist HX531 can improve insulin resistance and obesity by inhibition of the function of PPAR-RXR heterodimer. Therefore, its pharmaceutical application to type II diabetes is expected (Nonpatent document No. 5).
Actions of RXR agonist are not limited to those mediated by a nuclear receptor heterodimer containing RXR. For example, concerning tamoxifen used for treating breast cancer, while its molecular target is estrogen receptor (ER), which does not form a heterodimer with RXR, RXR agonist has been reported to improve the resistance of estrogen-resistant breast cancer (Nonpatent document No. 6). Preventative effect on carcinogenesis has also been reported by RXR agonist alone or in combination with tamoxifen (Nonpatent document No. 7). Further, effects of RXR agonist on Taxol-resistant cancer has been reported (Nonpatent document No. 8). In addition, the action of RXR agonist to inhibit angiogenesis has also been reported (Nonpatent document No. 9).
Further, the administration of RXR agonist alone even shows an interesting physiological activity. For example, when RXR agonist is administered to mouse models of type II diabetes, the improved insulin resistance and the reduced blood glucose level has been reported (Nonpatent document No. 10).
Further, RXR agonist acts on hair-root cycle to show hair growing effect, and thus its application as a hair restorer has also been reported (Patent document No. 1).
RXR agonists and antagonists are generally referred to as rexinoid. Conventionally developed rexinoid compounds are often highly lipid-soluble (log P>7), so that there remains an anxiety that teratogenicity could be caused by its accumulation in body or its passage through placental barrier. Generally, rexinoid is a compound having in its partial structure a hydrophobic site characterized by a tetramethyltetrahydronaphthyl group as represented by the general formula III and an acidic site consisting of benzoic acid and like (Nonpatent document Nos. 11 and 12, patent document No. 2). For example, compound LGD1069, wherein X is C═CH2; R is a methyl group; and Y and Z are CH, has been known (Nonpatent document No. 13), but they are all highly lipid-soluble.
It has been known that RXR has three subtypes (α, β and γ) (Nonpatent document No. 14). However, ligands selective for those subtypes have not been synthesized to date (Nonpatent document No. 15).
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